Cognition and beta-amyloid in preclinical Alzheimer's disease: Data from the AIBL study

Pike, Kerryn E.; Ellis, Kathryn A.; Villemagne, Victor L.; Good, Norm; Chételat, Gaël; Ames, David; Szoeke, Cassandra; Laws, Simon M.; Verdile, Giuseppe; Martins, Ralph N.; Masters, Colin L.; Rowe, Christopher C.

doi:10.1016/j.neuropsychologia.2011.04.012

Cited by 138 publications

(119 citation statements)

References 52 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…Development of a multivariate model incorporating EYO and disease biomarkers, such as fibrillar amyloid levels, may enable cognitive decline to be predicted with greater precision. Most prior studies of cognitively healthy older people demonstrated episodic memory decline associated with amyloid burden in the brain 7,[10][11][12][13]15,18,20,21,23 earlier than other cognitive domain declines. 12,20,23 A meta-analysis including 16 independent cohorts (maximum of 1,278 participants) assessed the amyloid-cognition relationship in cognitively normal adults, and the results also showed that only episodic memory had a modest but significant negative relationship to amyloid burden detected by PiB-PET in presymptomatic AD.…”

Section: Discussionmentioning

confidence: 98%

“…[3][4][5][6] Studies using amyloid PET in cognitively normal elderly individuals and individuals with mild cognitive impairment (MCI) and AD dementia have found significant relationships between cognitive deficits and increased brain fibrillar amyloid using both cross-sectional [7][8][9][10][11][12] and longitudinal data [13][14][15][16][17][18][19][20][21][22][23] ; however, other studies have not shown amyloid and cognitive correlations. [24][25][26] In autosomal dominant AD (ADAD), brain amyloid deposition is known to occur 15 years or more before the onset of clinical symptoms, 27,28 and estimated years from expected symptom onset (EYO) calculated from family history data can provide an objective biomarkerindependent estimate of an individual's relative point in the disease process.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

et al. 2015

Self Cite

View full text Add to dashboard Cite

Objective: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD).Methods: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years 6 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE e4 allelic status, and education.Results: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination.Conclusions: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials. b-Amyloid (Ab) is thought to be an initiating factor in the pathophysiologic process of Alzheimer disease (AD).1,2 However, the relationship between cognition, brain Ab burden, and the future development of dementia is still unclear.

show abstract

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…34,35 In contrast, most (but not all 36 ) studies have found associations between Ab and accelerated memory decline in CN 37,38 and both baseline and longitudinal memory deficits in MCI. 39 Study limitations include that the use of a binary cutoff for Ab may fail to appreciate differences in degree of Ab pathology and the use of global Ab hinders us from detecting subtle regional differences that may be important in early disease stages.…”

Section: 12mentioning

confidence: 96%

Brain structure and function as mediators of the effects of amyloid on memory

et al. 2015

View full text Add to dashboard Cite

Objective: The objective of this study was to test whether effects of b-amyloid (Ab) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease.Methods: This was a prospective cohort study. We measured baseline Ab (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Ab positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n 5 280) and mild cognitive impairment (MCI, n 5 463).Results: Lower memory scores were associated with Ab positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Ab in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p , 0.05) with Ab positivity.Conclusions: Changes in brain structure and function appear to be, in part, downstream events from Ab pathology, ultimately resulting in episodic memory deficits. However, Ab pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease-like brain changes independently of Ab pathology. Alzheimer disease (AD)-like changes in brain structure and function may be present in the absence of biomarker evidence of b-amyloid (Ab) pathology.1 Therefore, it would be useful to quantify to what extent effects of Ab on cognition are explained by brain structure and function and to quantify the strength of Ab-independent associations between cognition and brain injury biomarkers. In this study, we tested the hypotheses that (1) Ab, and brain structure and function were associated with episodic memory deficits, (2) effects of Ab on episodic memory were mediated by brain structure and function, and (3) brain structure and function had Ab-independent effects on memory. Previous studies examining the relationships among Ab, cognition, and brain structure and function have mainly analyzed hippocampus, the ventricles, or whole brain lobes in combined or small cohorts of healthy controls (CN), patients with mild cognitive impairment

show abstract

“…12,14,36 Even if all amyloid-related variance in memory performance estimated here was shared with the age-related variance in memory, approximately 50% of the age-related variance would remain unexplained. The correlation between age and amyloid in cognitively normal adults is likely to be approximately 0.3 to 0.4 36,37 ; therefore, a more likely estimate is that approximately 80% of the age-related variance will remain unexplained by amyloid burden. It is likely that genetic factors, such as APOE allele status, will affect the relationship among aging, amyloid burden, and cognition.…”

mentioning

confidence: 99%

“…It is likely that genetic factors, such as APOE allele status, will affect the relationship among aging, amyloid burden, and cognition. [37][38][39][40] Additionally, the preclinical impact of other types of age-related neurodegeneration on cognitive function during aging remains an important area of exploration. [41][42][43][44][45] The studies analyzed primarily involved assessments of amyloid burden without regional specificity.…”

mentioning

confidence: 99%

Meta-analysis of amyloid-cognition relations in cognitively normal older adults

et al. 2013

View full text Add to dashboard Cite

Objective: We conducted a meta-analysis of relationships between amyloid burden and cognition in cognitively normal, older adult humans.Methods: Methods of assessing amyloid burden included were CSF or plasma assays, histopathology, and PET ligands. Cognitive domains examined were episodic memory, executive function, working memory, processing speed, visuospatial function, semantic memory, and global cognition. Sixty-four studies representing 7,140 subjects met selection criteria, with 3,495 subjects from 34 studies representing independent cohorts. Weighted effect sizes were obtained for each study. Primary analyses were conducted limiting to independent cohort studies using only the most common assessment method (Pittsburgh compound B). Exploratory analyses included all assessment methods.Results: Episodic memory (r 5 0.12) had a significant relationship to amyloid burden. Executive function and global cognition did not have significant relationships to amyloid in the primary analysis of Pittsburgh compound B (r 5 0.05 and r 5 0.08, respectively), but did when including all assessment methods (r 5 0.08 and r 5 0.09, respectively). The domains of working memory, processing speed, visuospatial function, and semantic memory did not have significant relationships to amyloid. Differences in the method of amyloid assessment, study design (longitudinal vs cross-sectional), or inclusion of control variables (age, etc.) had little influence.Conclusions: Based on this meta-analytic survey of the literature, increased amyloid burden has small but nontrivial associations with specific domains of cognitive performance in individuals who are currently cognitively normal. These associations may be useful for identifying preclinical Alzheimer disease or developing clinical outcome measures.

show abstract

Cognition and beta-amyloid in preclinical Alzheimer's disease: Data from the AIBL study

Cited by 138 publications

References 52 publications

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease

Brain structure and function as mediators of the effects of amyloid on memory

Meta-analysis of amyloid-cognition relations in cognitively normal older adults

Contact Info

Product

Resources

About